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. 2023 Jun 1;9(6):779-789.
doi: 10.1001/jamaoncol.2023.0147.

Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: The Phase 2 CheckMate 714 Randomized Clinical Trial

Kevin J Harrington  1 , Robert L Ferris  2 , Maura Gillison  3 , Makoto Tahara  4 , Athanasios Argiris  5   6 , Jérôme Fayette  7   8 , Michael Schenker  9 , Åse Bratland  10 , John W T Walker  11 , Peter Grell  12 , Caroline Even  13 , Christine H Chung  14 , Rebecca Redman  15 , Alexandre Coutte  16 , Sébastien Salas  17 , Cliona Grant  18 , Sergio de Azevedo  19 , Denis Soulières  20 , Aaron R Hansen  21 , Li Wei  22 , Tariq Aziz Khan  22 , Karen Miller-Moslin  22 , Mustimbo Roberts  22 , Robert Haddad  23
Affiliations

Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: The Phase 2 CheckMate 714 Randomized Clinical Trial

Kevin J Harrington et al. JAMA Oncol. .

Abstract

Importance: There remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

Objective: To evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN.

Design, setting, and participants: The CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from October 20, 2016 (first patient, first visit), to March 8, 2019 (primary database lock), and April 6, 2020 (overall survival database lock).

Interventions: Patients were randomized 2:1 to receive nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal.

Main outcomes and measures: The primary end points were objective response rate (ORR) and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory R/M SCCHN. Exploratory end points included safety.

Results: Of 425 included patients, 241 (56.7%; median age, 59 [range, 24-82] years; 194 males [80.5%]) had platinum-refractory disease (nivolumab plus ipilimumab, n = 159; nivolumab, n = 82) and 184 (43.3%; median age, 62 [range, 33-88] years; 152 males [82.6%]) had platinum-eligible disease (nivolumab plus ipilimumab, n = 123; nivolumab, n = 61). At primary database lock, the ORR in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%-19.5%) with nivolumab plus ipilimumab vs 18.3% (95% CI, 10.6%-28.4%) with nivolumab (odds ratio [OR], 0.68; 95.5% CI, 0.33-1.43; P = .29). Median duration of response for nivolumab plus ipilimumab was not reached (NR) (95% CI, 11.0 months to NR) vs 11.1 months (95% CI, 4.1 months to NR) for nivolumab. In the population with platinum-eligible disease, the ORR was 20.3% (95% CI, 13.6%-28.5%) with nivolumab plus ipilimumab vs 29.5% (95% CI, 18.5%-42.6%) with nivolumab. The rates of grade 3 or 4 treatment-related adverse events with nivolumab plus ipilimumab vs nivolumab were 15.8% (25 of 158) vs 14.6% (12 of 82) in the population with platinum-refractory disease and 24.6% (30 of 122) vs 13.1% (8 of 61) in the population with platinum-eligible disease.

Conclusions and relevance: The CheckMate 714 randomized clinical trial did not meet its primary end point of ORR benefit with first-line nivolumab plus ipilimumab vs nivolumab alone in platinum-refractory R/M SCCHN. Nivolumab plus ipilimumab was associated with an acceptable safety profile. Research to identify patient subpopulations in R/M SCCHN that would benefit from nivolumab plus ipilimumab over nivolumab monotherapy is warranted.

Trial registration: ClinicalTrials.gov Identifier: NCT02823574.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Harrington reported receiving personal fees from Bristol Myers Squibb, Arch Oncology, Codiak, Inzen, Merck Serono, MSD, Replimune, AstraZeneca, Boehringer Ingelheim, and Pfizer; receiving honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Merck Serono, and MSD; receiving meeting attendance and/or travel support from Merck Serono, MSD, and Replimune; participating in data safety monitoring board or advisory board meetings for Arch Oncology, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Codiak, Inzen, Merck Serono, MSD, Pfizer, and Replimune; and receiving grants from AstraZeneca, MSD, Boehringer Ingelheim, Replimune, and MSD. Dr Ferris reported receiving personal fees from Achilles Therapeutics, Adagene Inc, Aduro Biotech, Bicara Therapeutics, Bristol Myers Squibb, Brooklyn ImmunoTherapeutics LLC, Catenion, Coherus BioSciences, EMD Serono, Everest Clinical Research Corporation, F. Hoffmann-LaRoche, Genocea Biosciences, Hookipa Biotech, Instil Bio, Kowa Research Institute, Lifescience Dynamics Limited, MacroGenics, MeiraGTx LLC, Merck, Mirati Therapeutics, Nanobiotix, Novartis Pharmaceutical Corporation, Novasenta, Numab Therapeutics, Oncocyte Corporation, Pfizer, PPD Development, Rakuten Medical, Sanofi, Seagen, SIRPant Immunotherapeutics, Vir Biotechnology, and Zymeworks; receiving grants from AstraZeneca/MedImmune, Bristol Myers Squibb, Merck, Novasenta, and Tesaro; serving on the advisory board of Coherus BioSciences, Hookipa, Instil Bio, Lifescience Dynamics, MacroGenics, MeiraGTx LLC, Oncocyte Corporation, Pfizer, Rakuten Medical, Seagen, SIRPant Immunotherapeutics, and Vir Biotechnology; serving on the data safety monitoring board for and having stock in Mirror Biologics; having stock in or receiving stock options from Novasenta; serving on the advisory board for and receiving research funding from Numab Therapeutics; and serving as president-elect of the American Head and Neck Society. Prof Gillison reported receiving clinical trial support to the institution from Bristol Myers Squibb during the conduct of the study and from Gilead Sciences, Seagen, Bristol Myers Squibb, Genentech, Kura Oncology, and Agenus outside the submitted work; receiving personal fees from EMD Serono, Shattuck Labs, BioNTech, Kura Oncology, LLX Solutions, Eisai Medical Research, Ipsen Biopharmaceuticals, Nektar Therapeutics, Debiopharm, Coherus BioSciences, Mirati Therapeutics, Sensei Biotherapeutics, Seagen, Istari Oncology, iTeos Therapeutics, Caladrius Biosciences, Exelixis, Amgen, Aspyrian Therapeutics, AstraZeneca, Bayer, Bicara Therapeutics, Celgene, Genocea Biosciences, Gilead Sciences, Healthcare Pharmaceuticals, Merck, NewLink Genetics, OncLive Intellisphere, Roche, and TRM Oncology; receiving honoraria from OncLive and Roche; having patents issued for plasmid DNA and patents pending for oral human papillomavirus infection detection and screening; participating on data safety monitoring boards or advisory boards for BioMimetix, Kura Oncology, NRG, Seagen, Sensei Biotherapeutics, and SQZ Biotech; receiving options from Sensei Biotherapeutics; and receiving research funding to the institution from Agenus, Bristol Myers Squibb, Cullinan Labs, Genentech, Genocea Biosciences, Kura Oncology, LaRoche, NRG, and the University of Cincinnati. Dr Tahara reported receiving personal fees from Bristol Myers Squibb and grants from Ono Pharmaceutical during the conduct of the study; receiving personal fees from Bayer, Lilly, Merck, Pfizer, Rakuten Medical, Genmab, Nektar, Janssen, Astellas, Eisai, and MSD outside the submitted work; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Genmab, GlaxoSmithKline (GSK), Merck, MSD, Ono Pharmaceutical, Pfizer, and Rakuten Medical; and receiving grants or contracts to the institution from AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, GSK, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Rakuten Medical. Dr Argiris reported receiving research support from Bristol Myers Squibb and speaker fees from Merck. Dr Fayette reported receiving personal fees and nonfinancial support from MSD and AstraZeneca; grants, personal fees, and nonfinancial support from Bristol Myers Squibb; and personal fees from Innate Pharma, Roche, Hookipa, Merck, F-star, and Sanofi. Dr Schenker reported receiving grants from Bristol Myers Squibb during the conduct of the study and grants or fees from Eli Lilly, MSD, Roche, Novartis, Regeneron, Sanofi, Merck Serono, AstraZeneca, GSK, Amgen, Astellas, AbbVie, Bioven, BeiGene, Bayer, Clovis, Gilead, Mylan, Pfizer, PharmaMar, Samsung Pharmaceuticals, and Tesaro outside the submitted work. Dr Bratland reported receiving grants from Bristol Myers Squibb during the conduct of the study and from Merck Sharp & Dohme and GSK outside the submitted work; receiving personal fees from Sanofi for serving on the advisory board; and serving as president of the Scandinavian Society for Head and Neck Oncology. Dr Grell reported receiving funding from Bristol Myers Squibb during the conduct of the study and personal fees from Roche and Servier outside the submitted work. Dr Even reported receiving personal fees from Bristol Myers Squibb, MSD, and Merck Serono; travel fees from Bristol Myers Squibb and MSD; nonfinancial support from MSD and Merck Serono; and participating in data safety monitoring board or advisory board meetings for Bristol Myers Squibb, Merck Serono, Novartis, F-Star Therapeutics, and MSD. Dr Chung reported receiving a clinical trial contract from Bristol Myers Squibb to the Moffitt Cancer Center during the conduct of the study and personal fees for participating on ad hoc scientific advisory boards from Merck, Sanofi, Exelixis, Brooklyn ImmunoTherapeutics, Fulgent, GenMap, and Aveo outside the submitted work. Dr Redman reported receiving institutional funding from Bristol Myers Squibb during the conduct of the study and from Merck, Pfizer, Daiichi Sankyo, Iovance, Molecular Templates, RAPT Therapeutics, Inspirna, and ALX Oncology outside the submitted work. Dr Grant reported receiving honoraria from Bristol Myers Squibb. Dr de Azevedo reported participating in data safety monitoring board or advisory board meetings for Gilead Brazil. Dr Soulières reported receiving grants to the institution and personal fees for advisory board or clinical study board participation from Bristol Myers Squibb during the conduct of the study and from Merck and Adlai-Nortye outside the submitted work. Dr Hansen reported receiving research support to the institution from Bristol Myers Squibb, Merck, AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Janssen, Eisai, Novartis, POINT Biopharma, GSK, and MedImmune outside the submitted work and receiving consulting fees from Eisai, GSK, and Merck. Dr Wei reported receiving stocks from Bristol Myers Squibb. Dr Khan reported having stock in Bristol Myers Squibb. Dr Miller-Moslin reported having stock in Bristol Myers Squibb. Dr Roberts reported being employed by Takeda outside the submitted work. Dr Haddad reported receiving grants from Bristol Myers Squibb during the conduct of the study; receiving personal fees for consulting or advisory board participation from Bristol Myers Squibb, Merck, EMD, Eisai, Celgene, Kura, AstraZeneca, Genentech, Boehringer Ingelheim, Exelixis, Blue DOT, and Nanobiotix outside the submitted work; having a leadership role in the National Comprehensive Cancer Network; receiving consulting fees from Achilles Therapeutics, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus BioSciences, Eisai, EMD Serono, Genentech, Gilead Sciences, GSK, Immunomic Therapeutics, Loxo, Merck, Mirati, Pfizer, and Vaccinex; receiving royalties or having patents or other intellectual property from UpToDate; receiving research funding to the institution from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Kura Oncology, Merck, and Pfizer; and receiving fees for serving as chair of the data safety monitoring board for 2 trials run by Nanobiotix and ISA Pharmaceuticals. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Primary database lock was March 8, 2019; overall survival (OS) database lock was April 6, 2020. AE indicates adverse event.
Figure 2.
Figure 2.. Progression-Free Survival (PFS) and Overall Survival (OS) in the Populations With Platinum-Refractory and Platinum-Eligible Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M SCCHN)
Progression-free survival was assessed by blinded independent central review. The minimum follow-up was 22.2 months for the population with platinum-refractory disease and 22.7 months for the population with platinum-eligible disease. Outcomes were assessed at OS database lock (April 6, 2020). Triangles and circles indicate censored values. HR indicates hazard ratio.
See this image and copyright information in PMC

Comment in

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